Cyclic carbonyl compounds

ABSTRACT

Certain fluorenone and anthraquinone compounds, each of which is 2-substituted by a carboxyl group or a salt, ester or optionally substituted amide thereof and each of which is optionally substituted in the 5,6-,7- or 8- position, by a second carboxyl group, salt, ester or optionally substituted amide thereof, the substitutent in the 5,6-7- or 8- position of the fluorenone compounds, also being selected from cyano, halogen, nitro, alkyl, alkoxy and acyl, are useful for the relief or prophylaxis of allergic conditions.

This application is a continuation-in-part of U.S. patent applicationSer. No. 287,042 filed Sept. 7, 1972, now pending.

The invention relates to tricyclic compounds having medicinalproperties, the synthesis of the compounds and their adaptation formedicinal use.

It has been found that tricyclic compounds of formula I definedhereinbelow are active in mammals and in in vitro mammalian preparationsas inhibitors of allergic reactions associated with reaginic antibodiesof the kind responsible for asthma in man, and that this effect isattributable to the suppression of the release of anaphylacticmediators.

In formual I ##SPC1##

Z¹ is a carboxyl group, a carboxylate salt group, an alkyl carboxylategroup wherein the alkyl moiety has 1 to 6, preferably 1 to 4 carbonatoms or a carboxamide group optionally N-substituted by alkyl having 1to 6, preferably 1 to 4 carbon atoms; Z³ represents a bond or is acarbonyl group; and Z² is a substituent and has the same meaning as Z¹or is a hydrogen atom or when Z³ is a bond, Z² is a nitro group, a cyanogroup, a halogen atom preferably chlorine or bromine, an acyl group, analkyl group or an alkoxy group wherein the "alkyl" moiety of each of theacyl, alkyl and alkoxy groups has 1 to 6 carbon atoms.

Especially active compounds of formula I are fluorenone-2,7-dicarboxylic acid and pharmaceutically acceptable salts thereof,especially Disodium fluorenone-2,7-dicarboxylate of formula ##SPC2##

As well as the dipotassium and diammonium salts ofFluorenone-2,7-dicarboxylic acid.

Highly active compounds of formula I are Anthraquinone-2,6-dicarboxylicacid and pharmaceutically acceptable salts thereof, especially thedisodium, dipotassium and diammonium salts thereof.

Substantially active compounds of formula I include:

7-Methoxyfluorenone-2-carboxylic acid;

7-Cyanofluorenone-2-carboxylic acid;

7-Ethylfluorenone-2-carboxylic acid; and pharmaceutically acceptablesalts thereof.

Other moderately active compounds of formula I include:

7-Chlorofluorenone-2-carboxylic acid;

7-Acetylfluorenone-2-carboxylic acid;

7-Carboxamidofluorenone-2-carboxylic acid;

7-Nitrofluorenone-2-carboxylic acid;

Fluorenone-2-carboxylic acid;

Anthraquinone-2-carboxylic acid; and pharmaceutically acceptable salsthereof.

The inhibition activity of the compounds of formula I has beendemonstrated (a) in tests using the response of passive cutaneousanaphylaxis (PCA test) in which is measured the skin reaction producedas the result of interaction between specific antigen injectedintravenously and cell-fixed reaginic antibody previously injected intothe skin of a mammal (see for example Z. Ovary: Fedn. Proc. Am. Soc.exp. Biol. 24, 94 (1965)), (b) by measurement of the amount of histaminereleased after antigen challenge of peritoneal mast cells from activelysensitised rats (see for example, 1. Acta Pharmacol. et Toxicol. 30,supp. 1 (1971), 2. Thorax, 27/1, 38 (1972), and (c), by measurement ofthe histamine released from human chopped lung tissue passivelysensitised in vitro with reaginic antibody when challenged with thehomologous antigen (Br. Med. J. 3,272 (1968)). The activity of acids offormula I has been demonstrated as described hereinabove using solutionsof the carboxylate anion.

For the sake of convenience, compounds of formula I wherein either of Z¹and Z² is or both are an alkyl carboxylate group, shall hereinafter bereferred to as `esters` of formula I. Similarly references to `amides`of formula I shall be construed as references to compounds of formula Iwherein one or both of Z¹ and Z² is an optionally substitutedcarboxamide, and references to `salts` of formula I shall mean compoundsof formula I wherein one or both of Z¹ and Z² is a carboxylate saltgroup.

Pharmaceutically acceptable salts of formula I include ammonium salts,alkali metal salts such as sodium and potassium salts, alkaline earthsalts such as magnesium and calcium salts, and salts of organic bases,for example, amine salts such as triethanolamine anddiethylaminoethylamine salts, and piperazine and morpholine salts.Especially valuable are water soluble salts of formula I most perferablythose having a solubility in water of at least 1 mg/ml.

The anti-allergic activity of the salts of formula I lies in the anionand the nature of the cation does not contribute to the activity, butfor medicinal purposes the cation must of course be pharmaceuticallyacceptable.

Suitable substituted carboxamide groups include N-alkyl and N,N-dialkylsubstituted carboxamide groups wherein the alkyl moiety is an alkylgroup having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.

Fluorenone compounds of the present invention include tricycliccompounds of formula ##SPC3##

wherein Z¹ and Z² are the same or different and each is selected from acarboxyl group, a carboxylate salt group, an alkyl carboxylate group,having 1 to 6 carbon atoms in the alkyl moiety, and a carboxamide groupoptionally N-substituted by an alkyl group having 1 to 6 carbon atoms.

Anthraquinone compounds of the present invention include tricycliccompounds of formula ##SPC4##

wherein Z¹ and Z² are the same or different and each is selected from acarboxyl group, a carboxylate salt group, an alkyl carboxylate grouphaving 1 to 6 carbon atoms, and a carboxamide group optionallyN-substituted by an alkyl group having 1 to 6 carbon atoms.

Novel fluorenone compounds of the present invention include tricycliccompounds of the formula ##SPC5##

wherein Z¹ is a carboxyl group or a carboxylate salt group and Z² is ahalogen atom, a cyano group, an alkyl group having 2 to 4 carbon atomsor a carboxamide group optionally N-substituted by alkyl having 1 to 6carbon atoms.

Novel compounds of the present invention also include solid tricycliccompounds of formula ##SPC6##

wherein Z² is a carboxylate salt group, Z³ represents a bond or is acarbonyl group, Z² is selected from a cyano group, a halogen atom, anitro group, an alkyl group, an acyl group or an alkoxy group whereinthe `alkyl` moiety of the alkyl, acyl and alkoxy groups is an alkylgroup having 1 to 6 carbon atoms.

The present invention also provides as novel products solid disodiumfluorenone-2,7-dicarboxylate, disodium fluorenone-2,7-dicarboxylatemonohydrate and particles of disodium fluorenone-2,7-dicarboxylatehaving a diameter of from 0.5 to 7μ.

Preparation of compounds of formula I may be effected by any methodknown in the art of preparing them and compounds of analogous chemicalstructure. In general the compounds of formula I wherein one or both ofZ¹ and Z² is a carboxylate derivative (for example an amide, ester orsalt), are prepared by suitable treatment of the corresponding acid.However, in certain circumstances it is possible to prepare suchderivatives without prior isolation of the carboxylic acid, either bythe choice of suitable reactants or by forming the desired derivative ina reaction mixture of the acid, without first isolating the acid.

Methods for the preparation of dicarboxylate acids and salts of formulaare described hereinbelow, but it will be understood that in someinstances the methods may be adopted to yield the corresponding estersor amides of formula I 1. Hydrolysis of a compound of formula XI##SPC7##

wherein Y¹ is a carboxyl group precursor, such as a nitrile group,trichloromethyl group or a group COL¹ wherein L¹ is a leaving group,such as a nucleophilic atom or group, for example, a trichloromethylgroup, an optionally substituted amino group, a halogen atom or analkoxy group; Y² is a carboxyl group or a group Y¹ precursor as definedabove; and Z³ has the meaning defined in formula I. Hydrolysis isconveniently effected by heating a compound of formula XI with a diluteaqueous alkali, or with a dilute aqueous mineral acid optionally with anorganic acid. For example, one may use dilute sulpuric acid, dilutehydrochloric acid with acetic acid, or dilute aqueous sodium hydroxidesolution. Hydrolysis with aqueous alkali will yield inter alia anaqueous solution of a dicarboxylate salt but if it is desired to collectthe maximum amount of dicarboxylic acid, then the reaction mixtureshould be acidified when hydrolysis is completed to precipitate theacid. On the other hand if the desired end-product is the dicarboxylatesalt, then following hydrolysis, the cation of the desired salt may beadded to precipitate the desired salt by the common ion effect withoutprior isolation of the corresponding acid.

By means of nucleophilic substitution reactions analogous to hydrolysis,for example, alcoholysis and ammonolysis, compounds of formula I otherthan the dicarboxylic acid may be prepared directly from compounds offormula XI. Thus reaction of a compound of formula XI with anappropriate alcohol yields an ester of formula I, and reaction withammonia or an appropriate primary or secondary amine yields an amide offormula I. 2. Cyclisation of a compound of formula XII ##SPC8##

wherein Z¹, Z² and Z³ have the meaning defined in formula I and Q is ahydroxyl, alkoxy or an optionally substituted amino group, a halogenatom, or a RCO₂ group, a ROCO₂ group or a RSO₃ group wherein R is alkylor aryl. Cyclisation may be effected by heating a compound of formulaXII at an elevated temperature, for example up to about 300°C.Preferably heating is carried out in the presence of a Lewis acid underanhydrous conditions or a protonic acid, optionally in the presence of anon-polar solvent. Preferred Lewis acids include boron trifluoride andaluminium trichloride and preferred protonic acids include sulphuric,hydrochloric and polyphosphoric acids. If, however, Z² is a carboxylatesubstituent in the 5-position of the nascent compound of formula I,reaction conditions and/or the group Q must be chosen so as to avoidreaction of the group Z².

In the case of anthraquinone compounds of formula I cyclisation to formthe carbonyl linkage in the tricyclic nucleus may be effected to formeither of the two carbonyl linkages of the tricyclic anthraquinonenucleus. 3. Oxidation of a compound of formula XVII ##SPC9##

wherein W¹ and W² are each a lower alkyl group or a group C(:O)R whereinR is an optionally substituted lower alkyl group having 1 to 4 carbonatoms, or is OH, provided that W¹ and W² are not both C(:O)OH and Z³ hasthe meaning defined in formula I. Oxidation of compounds wherein W¹and/or W² are lower alkyl groups may be effected with such conventionaloxidising agents as acid or alkaline aqueous potassium permanganatesolution; chromium trioxide, for example, with acetic acid or sulphuricacid; oxygen in the presence of a conventional catalyst such as lead,cobalt and manganese salts, for example, lead acetates or aqueoussolutions of sodium dichromate.

Oxidation of compounds wherein W¹ and/or W² are the groups C(:O)R may beeffected with such conventional oxidising agents as chromium trioxide,for example, with acetic acid or sulphuric acid; aqueous solutions ofsalts of hypochlorous and hypobromous acids in the presence of a base;sodium or potassium dichromate with acetic acid; or nitric acid. Theseoxidation procedures are advantageously effected with heating in theliquid phase. 4. Oxidation of a compound of formula XVIII ##SPC10##

wherein Z¹ and Z² have the meaning defined hereinbefore in formula I, Y³is a group Z³ as defined hereinbefore in formula I and Y⁴ is a methylenegroup; or Y⁴ and Y³ are the same or different and are each selected fromCH and CR wherein R is lower alkyl. Oxidation of compounds of formulaXVIII may be effected with such conventional oxidising agents as nitricacid; aqueous solutions of hypochlorous and hypobromous acids in thepresence of base; chromium trioxide, for example with acetic acid orwith sulphuric acid; or aqueous solutions of sodium dichromate.

Oxidation of compounds of formula XVIII wherein Y⁴ is a methylene groupand Y³ is a bond, or Y⁴ and Y³ are each CH, may also be effected withsuch conventional oxidising agents as oxygen in the presence of triton Bin pyridine solution; or oxygen in the presence of potassium t-butoxidein the presence of t-butanol and dimethylsulphoxide.

Compounds analogous to the compounds of formula XVIII wherein either orboth of Z¹ and Z² is replaced by a group W¹ or W² as defined in formulaXVII, may also be oxidised so as to produce dicarboxylate acids or saltsof formula I. Oxidation in the case of such compounds may be effectedwith such conventional oxidising agents as chromium trioxide, forexample, with acetic acid or with sulphuric acid; or aqueous solutionsof sodium dichromate. In the case of such compounds wherein neither ofW¹ and W² is alkyl, oxidation may also be effected with suchconventional oxidising agents as aqueous solutions of salts ofhypobromous or hypochlorous acids in the presence of a base; or nitricacid. Advantageously any of the hereinbefore described oxidationprocedures wherein aqueous solutions of sodium dichromate are employed,are carried out at an elevated temperature in a sealed container.Oxidation of the groups W¹ and W² in such a case is preferably effectedat a temperature of from 200° to 210° C. Oxidation of the tricyclicanthracene; 9,10 -dialkyl anthracene or anthrone nucleus in such a caseis desirably effected at a temperature of from 250° to 260°C.

Pharmaceutically acceptable salts of acids of formula I are prepared byany conventional method, for example by neutralising the correspondingcarboxylic acid with an appropriate Bronsted base, or by doubledecomposition of a salt of an acid of formula I so as to produce thedesired salt of an appropriate pharmaceutically acceptable cation. Thecarboxylic acid may be either the isolated acid, or may be present insolution in the reaction mixture resulting from a preparation of theacid, for example by such a method as described hereinbefore. SuitableBronsted bases include organic bases such as ethanolamine, and basescontaining ammonium, and alkali metal and alkaline earth metal cations.Double decomposition may be effected advantageously in an ion exchangeresin wherein a solution of a salt of an acid of formula I is passedthrough a cation exchange resin, the resin being charged with apharmaceutically acceptable cation of the suitable base. Doubledecomposition may also be effected in ordinary solution between a saltof an acid of formula I and a salt of the desired pharmaceuticallyacceptable cation.

Specifically, pharmaceutically acceptable salts of Formula I may beprepared by one or more of the following methods.

1. Reaction in a polar medium of a compound of formula XXIII. ##SPC11##

wherein one of Y⁷ and Y⁸ is the hydrogen ion and the other representsthe hydrogen ion or a cation of the desired salt, with a base of thedesired salt, or when Y⁷ and Y⁸ represent together or separately asingle or two cations other than the cation of the desired salt, and Z³has the meaning in formula I.

2. reaction in a polar medium of a compound of formula XXIV ##SPC12##wherein Y⁷ and Y⁸ are the same or different and each is selected from acarboxylic group and a group Y¹ as defined hereinbefore in formula XI,and Z³ has the same meaning as before, with an appropriate Bronsted baseand, when the Bronsted base does not contain a hydroxyl ion, in thepresence of water. Examples of appropriate Bronsted bases are alkali andalkaline earth metal oxides and hydroxides for producing correspondingalkali and alkaline earth metal salts of formula I. Preferably thereaction is effected with heating.

Salts of formula I may be isolated from a reaction medium by anyconventional process for the isolation of salts from a solution thereofin a polar medium. Thus the salts may be isolated by precipitation ofthe salt or by removal of the polar medium.

Precipitation of the salt may be effected by mixed solventcrystallisation or by the addition of excess base or salt thereof so asto produce a concentration of the cation of the salt to be isolated,substantially in excess of the molar ratio thereof in said salt to beisolated.

Mixed solvent crystallisation may be effected by addition, to a solutionof a salt of formula I in a polar medium, of a second polar solventother than, but miscible with, the polar solvent already present and inwhich second solvent the salt of formula I is less soluble than in thepolar solvent already present.

Removal of the polar medium may be effected by evaporation, for example,by freeze-drying, or by azeotropic distillation.

Desirably the salts of formula I are purified prior to incorporation ina pharmaceutical composition. Purification may be effected by anyconventional method. A particularly valuable purification processcomprises isolation of a crude solid salt of formula I from a reactionmixture wherein said salt has been produced, by any method for theisolation of salts of formula I as described hereinabove; dissolution ofthe salt in hydrochloric acid; recovery of the corresponding acid offormula I as a solid; neutralisation of the acid of formula I with aBronsted base of which base the cation is the cation of the requiredsalt of formula I; removal of solid impurities by filtration; andisolation of the salt of formula I by a method as described hereinabove.

Conveniently an acid of formula I may be purified prior toneutralisation, by recrystallisation or by isolation of aN,N-dimethylformamide adduct and subsequently heating the adduct todrive off the N,N-dimethylformamide.

Esters and amides of acids of formula I may be prepared by anyconventional method including esterification of the acid or acidchloride with an alkyl alcohol to yield the corresponding alkyl ester,and reaction of the acid or acid chloride with ammonia or an alklyamineto yield the corresponding amide or N-alkyl substituted amiderespectively. Compounds of formula I where Z¹ and Z² are different andare chosen from acid, ester, amide and salt functions, may be preparedby the above methods, and by partial hydrolysis where appropriate.

The compounds of formula I are useful in the treatment or prophylaxis ofmammalian allergic conditions such as asthma and other allergic chestconditions, hay fever (allergic rhinitis), conjunctivitis, urticaria andeczema. In particular they are of value in reaginic antibody mediatedType I hypersensitivity asthma (`extrinsic asthma`) and the so-called`intrinsic asthma` in which no sensitivity to extrinsic antigen can beshown.

The magnitude of a prophylactic or therapeutic dose of a compound offormula I will of course vary with the nature and the severity of theallergic condition to be treated and with the particular compound offormula I and its route of administration. In general the dose rangelies within the range of 2 μg. to 100 mg. per kg. body weight of amammal.

In the case of an allergic condition as defined hereinbefore, forexample, allergic asthma, a suitable dosage is from 5 μg. to 0.5 mg.,preferably from 20 μg. to 0.2 mg., for example about 0.1 mg., of acompound of formula I, per kg. of bodyweight of the patient undergoingtreatment, when pulmonary administration as described hereinafter isemployed. In the case where a composition for intravenous administrationis employed a suitable dosage range is from 0.2 to 100 mg. of a compoundof formula I per kg. of bodyweight of patient, and in the case where anoral composition is employed a suitable dosage range is from 2 to 50 mg.of a compound of formula I per kg. of bodyweight of a patient.

In the case where a composition for nasal administration is employed,for example, in the treatment of allergic rhinitis, a suitable dose isfrom 2 μg to 4 mg. of a compound of formula I per kg. of body weight ofpatient.

In the case of fluorenone-2, 7 dicarboxylate salts, particularlysuitable dosages for the treatment of allergic asthma have been found tobe as follows, all doses being given on the basis of the weight of thefree dicarboxylic acid and as amounts per kg. of bodyweight of thepatient undergoing treatment: for allergic asthma by pulmonaryadministration 20 μg to 0.2 mg. preferably 0.1mg., by intravenousadministration 1 to 10mg. and by oral administration 10 to 40mg.; andfor allergic rhinitis by nasal administration 10 μg to 0.4mg.

The pharmaceutical compositions of the present invention comprise acompound of formula I as an active ingredient, and may also containpharmaceutically acceptable carrier and optionally other therapeuticingredients. The compositions include composition suitable for oral,rectal, opthalmic, pulmonary, nasal, dermal, topical, or parenteral(including subcutaneous, intramuscular and intravenous) administration,although the most suitable route in any given case will depend on thenature and severity of the condition being treated, and on the nature ofthe active ingredient. They may be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; or as a solution or a suspension inan aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or awater-in-oil liquid emulsion. Such compositions may be prepared by anyof the methods of pharmacy but all methods include the step of bringinginto association the active ingredient with the carrier whichconstitutes one or more accessory ingredients. In general thecompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into the desiredpresentation. For example a tablet may be prepared by compression ormoulding, optionally with one or more accessory ingredients. Compressedtablets may be prepared by compressing in a suitable machine, the activeingredient in a free-flowing form such as a powder or granules,optionally mixed with a binder, lubricant, inert diluent, lubricating,surface active or dispersing agent. Moulded tablets may be made bymoulding in a suitable machine, a mixture of the powdered compoundmoistened with an inert liquid diluent. Desirably, each tablet containsfrom 200mg. to 500mg. of the active ingredient, and each cachet orcapsule contains from 500 to 2000mg. of the active ingredient.

A particularly valuable form of a pharmaceutical composition of thepresent invention, for use in the treatment of allergic asthma, is acomposition suitable for pulmonary administration via the buccal cavity;although of course conditions other than allergic asthma may also betreated by pulmonary administration of the composition.

Preferably the composition is such that particles having a diameter of0.5 to 7μ; most preferably 1 to 6μ, containing active ingredient, aredelivered into lungs of a patient. This ensures that a maximal amount ofactive ingredient is administered to the alveolar sacs of the lungs andretained therein thus producing a maximal effect in the patient. Suchcompositions are most preferably in the form of dry powders foradministration from a powder inhalation device or self-propellingpowder-dispensing compositions.

Most preferably the powders of the pulmonary compositions as describedhereinabove and hereinbelow comprise particles containing activeingredient of which particles at least 98% by weight have a diametergreater than 0.5μ and at least 95% by number have a diameter less than7μ. Most desirably at least 95% by weight of the particles have adiameter greater than 1μ and at least 90% by number of the particleshave a diameter less than 6 μ.

The compositions in the form of dry powders preferably compriseparticles containing the solid active ingredient, the particles having adiameter of 0.5 to 7μ most preferably 1 to 6μ. Preferably thesecompositions include a solid diluent in the form of a fine powder. Thesecompositions may be conveniently presented in a pierceable capsule of apharmaceutically acceptable material, for example gelatin. Suchcompositions may be conveniently prepared by comminution of solid activeingredient optionally with a solid diluent. If desired the resultingpowder may be filled into a pierceable capsule of a pharmaceuticallyacceptable material.

Other valuable forms of a composition of the present invention that aresuitable for pulmonary administration are self-propelling compositions.These self-propelling compositions may be either powder-dispensingcompositions or compositions dispensing the active ingredient in theform of droplets of a solution or suspension.

Self-propelling powder-dispensing compositions preferably comprisedispersed particles of solid active ingredient, having a diameter of 0.5to 7μ most preferably 1 to 6μ and a liquid propellant having a boilingpoint of below 65°F at atmospheric pressure. The liquid propellant maybe any propellant known to be suitable for medicinal administration andmay comprise one or more lower alkyl hydrocarbons, or halogenated loweralkyl hydrocarbons, or mixtures thereof. Chlorinated and fluorinatedlower alkyl hydrocarbons are especially preferred as propellant.Generally the propellant may constitute 50 to 99.9% w/w of thecomposition whilst the active ingredient may constitute 0.1 to 20% w/w,for example, about 2% w/w, of the composition.

The pharmaceutically acceptable carrier in such selfpropellingcompositions may include other constituents in addition to thepropellant, in particular a surfactant or a solid diluent or both.Surfactants are desirable in preventing agglomeration of the particlesof active ingredient and in maintaining the active ingredient insuspension. Especially valuable are liquid non-ionic surfactants andsolid anionic surfactants or mixtures thereof. Suitable liquid non-ionicsurfactants are those having a hydrophile-lipophile balance (HLB, seeJournal of the Society of Cosmetic chemists Vol. 1 pp. 311-326 (1949))of below 10, in particular esters and partial esters of fatty acids withaliphatic polyhydric alcohols, for instance, sorbitan monooleate andsorbitan trioleate, known commercially as "Span 80" (Trade Name) and"Span 85" (Trade Name). The liquid non-ionic surfactant may constituteup to 20% w/w of the composition, though preferably it constitutes below1% w/w of the composition. Suitable solid anionic surfactants includealkali metal, ammonium and amine salts of dialkyl sulphosuccinate, wherethe alkyl groups have 4 to 12 carbon atoms, and alkylbenzene sulphonicacid where the alkyl group has 8 to 14 carbon atoms. The solid anionicsurfactants may constitute up to 20% w/w of the composition, thoughpreferably below 1% w/w of the composition.

Solid diluents may be advantageously incorporated in suchself-propelling compositions where the density of the active ingredientdiffers substantially from the density of the propellant; also in orderto help to maintain the active ingredient in suspension. The soliddiluent is in the form of a fine powder, preferably having a particlesize of the same order as that of the particles of active ingredients.Suitable solid diluents include sodium choride and sodium sulphate.

Compositions of the present invention may also be in the form of aself-propelling composition wherein the active ingredient is present insolution. Such self-propelling compositions may comprise an activeingredient, propellant and co-solvent, and advantageously an antioxidantstabiliser. The propellant is one or more of those already cited above.Co-solvents are chosen for their solubility in the propellant, theirability to dissolve the active ingredient, and for their having thelowest boiling point consistent with these above-mentioned properties.Suitable co-solvents are lower alkyl alcohols and ethers and mixturesthereof. The co-solvents may constitute 5 to 40% w/w of the composition,though preferably less than 20% w/w of the composition.

Antioxidant stabilisers may be incorporated in suchsolution-compositions to inhibit deterioration of the active ingredientand are conveniently alkali metal ascorbates or bisulfites. They arepreferably present in an amount of up to 0.25% w/w of the composition.

Such self-propelling compositions may be prepared by any method known inthe art. For example the active ingredient either as particles asdefined hereinbefore in suspension in a suitable liquid or in up to 20%w/v solution in an acceptable co-solvent as appropriate, is mixed withany other constituents of a pharmaceutically acceptable carrier. Theresulting mixture is cooled and introduced into a suitable cooledcontainer and propellant is added therto in liquid form; and thecontainer is sealed.

Alternatively, such self-propelling compositions may be prepared bymixing the active ingredient either in particles as hereinbefore definedor in 2 to 20% w/v alcohol or aqueous solution as appropriate, togetherwith the remaining constituents of the pharmaceutically acceptablecarrier other than propellant; introducing the resulting mixture,optionally with some propellant, into a suitable container; sealing thecontainer; and injecting propellant under pressure into the container atambient temperature through a valve which comprises a part of thecontainer and is used to control release of the composition from it.Desirably the container is purged by removing air from it at aconvenient stage in the preparation of the self-propelling composition.

A suitable container for a self-propelling composition, is one providedwith a manually operable valve and being constructed of aluminium,stainless steel or reinforced glass. The valve should of course be onehaving the desired spray characteristic, that is, the spray issuing fromthe valve should have the characteristics of particle size ashereinbefore defined. Advantageously the valve is of the metered type,that is a valve of the type which delivers a fixed amount of compositionon the occasion of each operation of the valve, for example, about 50 or100 microliters of composition in each delivery.

Compositions of the present invention may also be in the form of aqueousor dilute alcoholic solution, optionally a sterile solution, of theactive ingredient for use in a nebuliser or atomiser, wherein anaccelerated air stream is used to produce a fine mist consisting ofsmall droplets of the solution. Such compositions usually contain aflavouring agent such as saccharin sodium and a volatile oil. Abuffering agent such as sodium phosphate; an antioxidant such as sodiummetabisulfite; and a surface active agent may also be included in such acomposition. Desirably such a composition should contain a preservativesuch as methylhydroxybenzoate.

Compositions of the present invention suitable for parenteraladministration conveniently comprise sterile aqueous solutions of theactive ingredient, which solutions are preferably isotonic with blood ofa patient under treatment. These are preferably administeredintra-venously, although administration may also be effected by means ofsubcutaneous or intra-muscular injection. Such compositions may beconveniently prepared by dissolving solid active ingredient in water toproduce an aqueous solution, and rendering said solution sterile andisotonic with human blood.

Pharmaceutical compositions of the present invention suitable fortopical use include compositions suitable for administration to theskin, eyes, nose and mouth.

Compositions for use on the skin include lotions and creams comprisingliquid or semi-solid emulsions, either oil-in-water or water-in-oil,which preferably contain from 0.2 to 5% w/v of the active ingredient.Ointments comprising 0.2 to 5% w/v of the active ingredient dissolved ordispersed in a semi-solid basis may also be used for topicaladministration to the skin. Conveniently the semi-solid basis containsliquid or semi-solid hydrocarbons, animal fat, wool alcohol or amacrogol, possibly with an emulsifying agent. Desirably the creams andointments should contain a preservative such as methyl hydroxybenzoate.

Compositions for administration to the eye include eye drops comprisingthe active ingredient in an aqueous or oily solution, preferably at aconcentration of 0.2 to 5% w/v. Such solutions are desirably fungistaticand bacteriostatic and are preferably prepared sterile. Compositions foradministration to the eye also include eye ointments which preferablycomprise the same concentration of active ingredient, conveniently inthe form of a salt, either dissolved in one of the ingredients of thesemi-solid basis of the ointment or as a finely divided suspensiontherein.

Compositions suitable for administration to the nose include powderself-propelling and spray compositions similar to those alreadydescribed under compositions suitable for pulmonary administration buthaving when dispersed, a somewhat larger particle size of the order of10 to 200 microns. In the case of self-propelling solution and spraycompositions this effect may be achieved by choice of a valve having thedesired spray characteristic i.e. being capable of producing a sprayhaving the desired particle size or by incorporating the medicament as asuspended powder of controlled particle size. Thus the compositioninstead of passing into the lungs is largely retained in the nasalcavity. Other compositions suitable for nasal administration include acoarse powder having a particle size of 20 to 500 microns which isadministered in the manner in which snuff is taken i.e. by rapidinhalation through the nasal passage from a container of the powder heldclose up to the nose. Another composition suitable for nasaladministration is nasal drops comprising 0.2 to 5% w/v of the activeingredient in aqueous or oily solution.

Compositions suitable for topical administration in the mouth includelozenges comprising 10 to 100mg. of the active ingredient in a flavouredbasis, usually sucrose and acacia or tragacanth; and pastillescomprising 10 to 100mg. of the active ingredient in an inert basis suchas gelatin and glycerine; or sucrose and acacia.

Other therapeutic ingredients suitable for inclusion in the hereinbeforedescribed compositions, especially in the case of those compositionsintended for use in the treatment of allergic asthma, includebronchodilators. Any bronchodilator may be used in such a compositionalthough particularly suitable bronchodilators are isoprenaline,adrenaline, orciprenaline isoethanine and physiologically acceptableacid addition salts thereof, especially isoprenaline sulphate.Conveniently the bronchodilator is present in the composition in anamount of 0.1 to 50% w/w of the weight of active ingredient present.

The present invention provides pharmaceutical compositions comprising acompound of formula I as defined hereinbefore together with apharmaceutically acceptable carrier thereof.

Accordingly, the present invention provides a method of treatment of anallergic condition as hereinbefore defined comprising administration ofa prophylactic or a therapeutic dose of a compound of formula I.

In another aspect the present invention provides a self-propellingpharmaceutical composition comprising 0.1 to 20% w/w of a compound offormula I as defined hereinbefore in the form of solid particles havinga diameter of from 1 to 7μ, 0.01 to 20% w/w of surfactant and 50 to99.9% w/w of a liquid propellant having a boiling point of below 19°C atatmospheric pressure.

In further aspects the present invention provides:

compositions comprising a tricyclic compound of formula II or III asdefined hereinbefore in association with a pharmaceutically acceptablecarrier therefor;

The novel tricyclic compounds of formula VI as defined hereinbefore; and

the novel solid tricyclic compounds of formula X, as definedhereinbefore.

In another aspect the present invention provides a method of preparing apharmaceutical formulation suitable for use in the treatment in mammalsof allergic conditions as defined hereinabove characterised in that oneprepares a compound of formula I by any one of the processes describedhereinabove; and optionally converts a compound of formula I so-producedto another compound of formula I; and admixes a compound of formula Iso-produced with an inert carrier therefor.

The following preparations and examples illustrate the methods forpreparing compounds in accordance with the present invention, as well ascompounds and compositions of the present invention. In the examples andpreparations, all temperatures are in degrees Celsius. Where meltingpoints are not given for compounds of formula I, the compounds decomposeat temperatures below their melting points and/or their melting pointsare at temperatures above those readily determinable by conventionaltechniques.

REFERENCE PREPARATION 1 Fluorenone-2,6-dicarboxylic acid

Aluminium chloride (440 g), suspended in dry 1,2-dichloroethane (500ml), was stirred and treated dropwise, at 0°C, with acetic anhydride(162 ml, 175 g). The resulting solution was then added, with stirring at0°C, to a solution of fluorene (125 g) in 1,2-dichloroethane (700 ml).When the addition was completed, half of the dichloroethane was removedunder reduced pressure and the residue was poured into a mixture of iceand 2N-hydrochloric acid. The resulting solid was collected byfiltration, washed with water, dried and recrystallised from acetone togive 2,7-diacetylfluorene, m.p. 177-180°.

Finely ground 2,7-diacetylfluorene (75.6 g) was added to a stirredsolution of sodium hydroxide (14 g) in 4.5% aqueous sodium hypochlorite(3.5 liter). The mixture was heated to 80°C for 5 hours and then cooledand filtered. The solid thus obtained was treated with hot water (1liter), filtered to remove unreacted 2,7-diacetylfluorene, and thefiltrate washed twice with dichloromethane and then acidified withconcentrated hydrochloric acid. The resulting pale yellow precipitatewas filtered, washed well with water and dried, to give purefluorenone-2,7-dicarboxylic acid, m.p. 410°C (decomp).

REFERENCE PREPARATION 2 Anthraquinone-2,6-dicarboxylic acid

Sodium nitrite (6.82 g.) was added to concentrated sulphuric acid (54.1ml) at 0°C with vigorous stirring and external cooling. The solution waswarmed to 50°-60°C and 2,6-diaminoanthraquinone (11.60 g.) was added insmall portions with stirring. The reaction mixture was heated at50°-60°C for 30 minutes, cooled to 30°C and poured onto ice (150g.). Theyellow tetrazonium salt was filtered off and washed with a little coldwater.

Cuprous cyanide solution was prepared according to the method in "A TextBook of Practical Organic Chemistry" p. 584, A. I. Vogel, Longmans(1948), from cupric sulphate pentahydrate (17g.), sodium metabisulphite(4.70 g.) and potassium cyanide (4.70g.).

To the cuprous cyanide solution was added the solid tetrazonium salt insmall portions at 60°-70°C. Frothing due to the evolution of nitrogenoccured. When the addition was complete, the reactants were heated on asteam bath for 25 minute to complete the reaction. The crude nitrile wasfiltered off as a brown solid, washed with water, and dried in an ovenat about 90°C. Infra-red spectrum (KBr disc) confirmed the presence ofnitrile (.sup.νC.tbd.N 2100 cm⁻ ¹).

Due to the very low solubility of the crude nitrile in common solvents,it was not possible to purify the nitrile by recrystallisation.Accordingly the crude nitrile was hydrolysed directly by boiling withaqueous sodium hydroxide (40g. in 300 ml. of water), for 7 hours. Aftercooling the reaction mixture was acidified with excess dilutehydrochloric acid, and the crude acidic product filtered off and washedwith water.

Three recrystallisations from dimethylformamide yielded pureanthraquinone-2,6-dicarboxylic acid (1.37g.) after drying at 156°C underpressure of 15 mm. of mercury in a drying pistol. The melting point wasabove 400°C.

REFERENCE PREPARATION 3 Anthraquinone-2,6-dicarboxylic acid

2,6-Dimethylanthracene (3.09g.), sodium dichromate (21.0g.) and water(75 ml.) were heated together at 215°C in an autoclave for 20 hours. Theresulting mixture was filtered to remove chromic oxide and the liquorsacidified with excess hydrochloric acid. The precipitated acid wasfiltered off and dried to yield a dark brown solid (1.14g.). The crudematerial was recrystallised from dimethylformamide and dried at 156°Cunder a pressure of 15 mm. of mercury to yield anthraquinone-2,6-dicarboxylic acid.

REFERENCE PREPARATION 4 Anthraquinone-2,6-dicarboxylic acid

2,6-Dimethylanthraquinone (15.4g.), chromium troxide (78.0g.) andglacial acetic acid (675 ml.) were boiled together under reflux for 64hours. On cooling the product crystallised out and was filtered off andwashed with water. The crude acid was recrystallised fromdimethylformamide and dried at 110°C for 3 days to yieldanthraquinone-2,6-dicarboxylic acid. Chemical analysis of the product:found Carbon 64.69% and Hydrogen 3.15% by weight.

REFERENCE PREPARATION 5 Fluorenone-2-carboxylic acid

A solution of 2-acetylfluorene (86 g.) in acetic acid (1075 ml.) at 60°was treated slowly with sodium dichromate (1020 g.), and then withacetic anhydride (285 ml.). The mixture was heated to reflux withstirring for 3 hours, cooled and poured into water (6 l.), and theprecipitate was filtered and washed well with water. This solid waswarmed with N-sodium hydroxide (520 ml.) and the mixture was filtered.The aqueous filtrate was washed three times with dichloromethane (3 × 60ml.) and then heated on the steam-bath and cautiously acidified withhydrochloric acid. The yellow product was filtered, washed well withwater and dried in vacuo to give fluorenone-2-carboxylic acid m.p. >300°.

REFERENCE PREPARATION 6 Anthraquinone-2-carboxylic acid

2-Methylanthraquinone (3 g.) was dissolved in sulphuric acid (15 ml) andthe solution cooled and diluted with water (15 ml). The mixture was thencooled and stirred vigorously during the portionwise addition of poweredsodium dichromate (9 g.) and finally heated on the steam-bath for 3hours, cooled and treated with water (100 ml.). The precipitated solidwas filtered washed well with water and treated with hot dilute aqueousammonia (60 ml. water and 2 ml. of 0.880 ammonia). The solution wasfiltered hot and acidified with hydrochloric acid; the pale yellowprecipitate was filtered, washed with water and dried to giveanthraquinone-2-carboxylic acid, m.p. 291°-292° unchanged byrecrystallisation from dimethylformamide.

REFERENCE PREPARATION 7 Anthraquinone-2,7-dicarboxylic acid

2,7-Dimethyl anthraquinone (5.15g, 21.8 m.mole) was refluxed withchromium trioxide (26.00g, 200% excess) in glacial acetic acid (250 ml)for 65 hours. The dark green solution was cooled in an ice-bath and thedeposited material was filtered off. This was washed with glacial aceticacid, and then with water to give a pale green solid which was dried at100°.

The crude material was then recrystallised from boilingdimethylformamide, treated with decolorising charcoal, and filtered atthe boil. The solid which separated on cooling was filtered off, washedwith a little ice-cold dimethylformamide, and dried under vacuum at155°C. The product, anthraquinone-2, 7-dicarboxylic acid, had a m.p.399°-401°(decomp.).

REFERENCE PREPARATION 8 Methyl fluorenone-2-carboxylate

Fluorenone-2-carboxylic acid (3 g.) in dry methanol (150 ml.) wastreated with sulphuric acid and the mixture was refluxed with stirringfor 72 hours and allowed to cool. The yellow precipitate was filtered,washed well with methanol, then with water, and dried to give methylfluorenone-2-carboxylate, m.p. 182°-185°.

REFERENCE PREPARATION 9 7-Nitrofluorenone - 2 -carboxylic acid

A solution of 2-acetyl-7-nitrofluorene (1.4g) in acetic acid (100ml) wastreated protionwise with sodium dichromate (6.85g.), then with aceticanhydride (5ml), and heated to reflux for 8 hours. The reaction mixturewas cooled somewhat, poured into hot water (600ml) and then cooled andfiltered. The resulting solid was warmed with 0.5% aqueous potassiumhydroxide and filtered hot, to give a filtrate which was acidified withhydrochloric acid. The precipitated acid was separated by filtration,washed well with hot water and dried in vacuo to give7-nitrofluorenone-2-carboxylic acid, m.p. 325°-327°.

REFERENCE PREPARATION 10 Disodium anthraquinone-2,6-dicarboxylate

Anthraquinone-2,6-dicarboxylic acid (0.50g) was dissolved in sodiumcarbonate solution (1 equivalent of sodium carbonate, 0.18g, in water,100 ml) with warming. As the di-sodium salt did not separate on cooling,the solution was evaporated to approximately 1/3 volume and heavilydiluted with ethanol. The solid which separated was filtered off, driedat 100°C. and analysed for the dihydrate. Analysis:

Required Carbon 51.09, Hydrogen 2.68,

Found Carbon 50.67, Hydrogen 2.78.

REFERENCE PREPARATION 11 7-Methoxyfluorenone-2-carboxylic acid

A suspension of 2-acetyl-7-methoxyfluorene (1.2g.) in a solution of 5%aqueous sodium hypochlorite (50ml.) containing sodium hydroxide (200mg.)was stirred and heated for 5 hours at 80°, and then cooled to 0° andfiltered, the filtrate being discarded. The precipitate consisted ofstarting material and the sodium salt of the product: it was treatedwith hot water (50ml., 25ml and 25ml, successively) and filtered hot;the combined filtrates were acidified with hydrochloric acid and theprecipitate was filtered, washed with water and dried in vacuo.Recrystallisation from a mixture of dimethylformamide and ethanol gave7-methoxyfluorenone-2-carboxylic acid, mp. >300°.

REFERENCE PREPARATION 12 Fluorenone-2,7-dicarboxamide

Flourenone-2,7-dicarboxylic acid (20g.) was suspended in thionylchloride (275ml.) containing dimethylformamide (lm.) and the mixture washeated to reflux for 3 hours. The resulting solution was evaporated todryness under reduced pressure and the residual solid was recrystallisedfrom toluene (200ml.). A portion (2g.) of this material was added to amixture of 0.880 ammonia solution (7ml.) and water (7ml.), and stirredfor 36 hours at room temperature. The total mixture was then stirred at100° for 4 hours; the solid was filtered suspended in water (100ml.) andheated to 100° for 8 hours. Finally, this mixture was cooled and thesolid was filtered, washed with water and dried to givefluorenone-2,7-dicarboxamide mp. >300°.

REFERENCE PREPARATION 13 Dimethyl fluorenone-2,7-dicarboxylate

A mixture of fluorenone-2,7-dicarboxylic acid (10g.), dry methanol(400ml.) and concentrated sulphuric acid (4ml.) was stirred and heatedto reflux for 72 hours. The mixture was cooled and filtered and thesolid was washed with methanol then with water, and dried in vacuo togive dimethyl fluorenone-2,7-dicarboxylate, mp. 223°-224°.

REFERENCE PREPARATION 14 7-Acetylfluorenone-2-carboxylic acid

This compound was prepared in known manner (Chemical Abstracts 1935, 29,1084 l ) and had a mp. >300°.

EXAMPLE 1 Disodium fluorenone-2,7-dicarboxylate

Fluorenone-2,7-dicarboxylic acid (10 g) was stirred with "Analar" (TradeName) sodium bicarbonate (6.28 g) and water (300 ml); warming gave aclear yellow solution which was evaporated under reduced pressure to ca.50 ml and treated with warm ethanol (500 ml). The resulting pale yellowsolid was collected and dried, to give disodiumfluorenone-2,7-dicarboxylate monohydrate.

The product obtained, having the following formula: ##SPC13##

(Synonym: Disodium 9-oxofluorene-2,7-dicarboxylate) provided, whendispersed in Nujol Mull, the infra-red spectrum shown in FIG. 1 appendedhereto.

EXAMPLE 2 Dipotassium fluorenone-2,7-dicarboxylate

Fluorenone-2,7-dicarboxylic acid (0.534 g) was dissolved in warm watercontaining Analar (Trade Name) potassium carbonate (0.544 g). The yellowsolution was concentrated, under reduced pressure, to 3 ml and treatedwith ethanol. The resulting pale yellow solid was collected and dried atambient temperature and pressure to give hydrated dipotassiumfluorenone-2,7-dicarboxylate.

EXAMPLE 3 Disodium fluorenone-2,7-dicarboxylate

A. Preparation of 2,7-Diacetylfluorene

Anhydrous aluminium chloride (872 g.) was suspended in1,2-dichloroethane (750 ml.), the mixture stirred with cooling in anice-salt bath, and acetic anhydride (282 ml.) added at such a rate as tomaintain the internal temperature between 0° and 10°C. When the additionwas complete a solution of fluorene (200 g.) in 1,2-dichloroethane (800ml.) was added dropwise maintaining the temperature below 20°C. Uponcompletion of the addition, the cooling bath was removed and the mixturestirred for two hours at ordinary temperature, after which the coolingbath was replaced and sufficient 3N-hydrochloric acid added slowly togive two clear phases without any solid in suspension.

The mixture was distilled under reduced pressure to remove all of theorganic solvent and the solid collected by filtration; the crude productwas washed thoroughly with water on the filter and dried in an oven atabout 100°C, before crystallising from boiling toluene to give2,7-diacetylfluorene m.p. 180°C.

B. Preparation of Disodium salt of fluorenone-2,7-dicarboxylic acid

Finely ground 2,7-diacetylfluorene (30 g.) was suspended in sodiumhypochlorite solution (1.0 l.; about 8% available chlorine) and thestirred suspension heated to 90°C. Heating was continued for 5 hoursallowing the chloroform formed in the reaction to distil out. At the endof the 5 hours sodium chloride (100 g.) was added and the stirredsuspension cooled to about 30°C and the solid collected by filtration.The solid was transfered to a flask, water (500 ml.) added, heated toabout 80°C and the solution filtered to remove unreacted2,7-diacetylfluorene. The filtrate was warmed to 40°C and an excess ofsodium chloride added to precipitate the disodium salt offluorenone-2,7-dicarboxylic acid.

EXAMPLE 4 Fluorenone-2,7-dicarboxylic acid, disodium salt

Fluorenone-2,7-dicarboxylic acid (30 g.) was suspended in water (300ml.) with stirring and neutralised with sodium hydroxide solution (about10%).

Charcoal (3 g.) was added to the solution and stirred at ambienttemperature for 30 minutes, after which the mixture was filtered througha Hyflo (Trade Name) bed.

The filtrate was placed in a clean beaker and 1200 ml. of filteredmethanol added to precipitate the solid disodium salt which wascollected by filtration, suspended with stirring in filtered methanol,collected, washed with methanol and dried at 100°C in a vacuum oven togive solid disodium fluorenone-2,7-dicarboxylate.

EXAMPLE 5 Fluorenone-2,7-dicarboxylic acid monosodium salt

Fluorenone-2,7-dicarboxylic acid disodium salt monohydrate (9.906 g.)was dissolved in water (50 ml.) The solution was stirred and treatedduring 15 minutes with successive drops of 5N hydrochloric acid (6 ml),stirred for a further 15 minutes at room temperature and then for 1 hourat 50°C. The mixture was cooled and filtered and the pale yellow solidwas washed and dried in vacuo to give fluorenone-2,7-dicarboxylic acidmonosodium salt monohydrate, which when dispersed in Nujol Null,provided the infra-red spectrum shown in FIG. 2 appended hereto.

EXAMPLE 6 Fluorenone-2,7-dicarboxylic acid calcium salt

Fluorenone-2,7-dicarboxylic acid disodium salt monohydrate (2 g.) wasdissolved in water (10 ml) with gentle warming, stirred and treated witha solution of calcium nitrate (3 g.) in a little water. The mixture waswarmed for a few minutes and the pale yellow precipitate was filtered,washed with water, and dried at ambient temperature and pressure to givefluorenone-2,7-dicarboxylic acid calcium salt dihydrate, which whendispersed in Nujol Mull, provided the infra-red spectrum in FIG. 3appended hereto.

EXAMPLE 7 Fluorenone-2,7-dicarboxylic acid disodium salt

A solution of fluorenone-2,7-dicarboxylic acid disodium salt monohydrate(2 g.) in warm water (10 ml.) was stirred and treated with magnesiumnitrate (1.7 g.) dissolved in water. The resulting pale yellowprecipitate was filtered, washed with water, and dried at ambienttemperature and pressure to give fluorenone-2, 7-dicarboxylic acidmagnesium salt dihydrate which when dispersed in Nujol Mull, providedthe infra-red spectrum shown in FIG. 4 appended hereto.

EXAMPLE 8 Fluorenone-2,7-dicarboxylic acid dipotassium salt

Fluorenone-2,7-dicarboxylic acid (4.0 g.) was added in portions to astirred solution of potassium carbonate (2.06 g.) in water (30 ml.) andstirring was then continued overnight at room temperature. The resultingsolution was treated with an excess of ethanol to precipitate a yellowsolid which was filtered washed with ethanol, and dried in vacuo at 100°to give anhydrous fluorenone-2,7-dicarboxylic acid dipotassium salt,which when dispersed in Nujol Mull, provided the infra-red spectrumshown in FIG. 5 appended hereto.

EXAMPLE 9 Fluorenone-2,7-dicarboxylic acid diammonium salt

Fluorenone-2,7-dicarboxylic acid (2 g.) was suspended in water (40 ml),treated with an excess of 0.880 ammonia and warmed to 50°C withstirring. After 45 minutes the solid had dissolved and the solution wastreated with ethanol (150 ml) and cooled to 0°C. The yellow solid wasfiltered and dried in vacuo to give anhydrousfluorenone-2,7-dicarboxylic acid diammonium salt, which when dispersedin Nujol Mull provided the infra-red spectrum shown in FIG. 6, appendedhereto.

EXAMPLE 10 Fluorenone-2-carboxamide

Fluorenone-2-carbonyl chloride (2.5 g.) was added in one portion torapidly stirred 0.880 ammonia (25 ml.). Stirring was continued for 3hours at room temperature and then for 5 hours at 50°. The solid wasfiltered, washed with water, dried, and recrystallised from a mixture ofdimethylformamide and ethanol to give deep yellow crystals offluorenone-2-carboxamide, m.p. 252°-254°.

EXAMPLE 11 7-Chloro-fluorenone-2-carboxylic

2-Acetyl-7-chlorofluorene (4g.), dissolved in acetic acid (40 ml.) at60°, was treated with sodium dichromate (25 g.) in ca. 5 g. portions.The mixture was refluxed for 5 hours, cooled and poured into cold water(1 l.). The precipitated solid was filtered, washed well with water andstirred at room temperature with a 10% solution (50 ml.) of 0.880ammonia in water. The mixture was filtered and the solid re-extractedwith a 2% solution (50 ml.) of 0.880 ammonia in water. Acidification ofthe combined ammoniacal extracts with sulphuric acid gave7-chloro-fluorenone-2-carboxylic acid, m.p. > 300°.

EXAMPLE 12 7-Bromo-fluorenone-2-carboxylic acid

2-Acetyl-7-bromofluorene (4 g.) in hot acetic acid (40 ml.) was treatedportionwise, over 45 minutes, with sodium dichromate (25 g.), then withacetic anhydride (7.5 ml). The mixture was heated to reflux for 5 hoursand then worked up as described in the previous Example to give7-bromo-fluorenone-2-carboxylic acid, m.p. > 300°.

EXAMPLE 13 7-Cyano-fluorenone-2-carboxylic acid

A mixture of 2-acetyl-7-bromofluorene (13.2 g.) and cuprous cyanide (8.2g.) in quinoline (40 ml.) was heated to reflux for 40 minutes, cooled to100° and poured into a mixture of ice-cold dilute aqueous ammonia anddichloromethane. The organic layer was separated, filtered to remove ayellow solid, washed with N-hydrochloric acid, dried over sodiumsulphate and evaporated. The residual solid was recrystallised fromethanol containing a small amount of dimethylformamide to give2-acetyl-7-cyanofluorene m.p. 182°-188°.

2-Acetyl-7-cyanofluorene (2.33 g.) was added to 5% aqueous sodiumhypochlorite (160 ml.) containing sodium hydroxide (400 mg.) andchloroform (5 ml.) and the mixture was stirred at 70°-80° for 7 hours,and then cooled and filtered. The precipitate was separated, digestedwith hot water (200 ml.) and filtered hot to give a solution which wasacidified with hydrochloric acid. The resulting solid was filtered,washed with hot water and dried in vacuo to give7-cyanofluorenone-2-carboxylic acid m.p. > 300°.

EXAMPLE 14 7-Ethyl-fluorenone-2-carboxylic acid

Acetic anhydride (2.67 g.) in dichloroethane (10 ml.) was added deopwiseto a stirred, cooled (0°) suspension of aluminum chloride (6.95 g.) indichloroethane (20 ml.). Cooling and stirring were continued during thedropwise addition of a solution of 2-ethylfluorene (4.61 g.) indichloroethane (50 ml.). The mixture was stirred for one hour at roomtemperature and then decomposed by the dropwise addition of2N-hydrochloric acid (40 ml.) to the cooled solution. The organic layerwas separated, washed with water and with aqueous sodium bicarbonate,dried over anhydrous sodium sulphate, filtered, and evaporated underreduced pressure. The residue was recrystallised from light petroleum(ca 250 ml., b.p. 60°-80°) to give 2-acetyl-7-ethylfluorene m.p.120°-122°.

A solution of sodium hypochlorite was prepared by the dropwise additionof bromine (27.5 g., 9.4 ml.) to a cooled (0°), stirred solution ofsodium hydroxide (17.2g.) in water (600 ml.). 2-Acetyl-7-ethylfluorene(6.74 g.) was added with stirring and the stirred mixture was warmed to70°, maintained at this temperature for 5 hours and allowed to standovernight at room temperature. The mixture was filtered and the filtratewas heated to 60° and treated with sodium acetate (300 g.). The sodiumsalt thus precipitated was filtered, dissolved in a minimum of hot waterand converted to the free acid with hydrochloric acid. The product wasfiltered, washed well with water and dried in vacuo to give pure7-ethylfluorenone-2-carboxylic acid m.p. > 300°, homogeneous by thinlayer chromatography.

EXAMPLE 15 7-Butyl-fluorenone-2-carboxylic acid

A mixture of 2-butyrylfluorene (11.3 g.), powdered potassium hydroxide(4.16 g.) and 100% hydrazine hydrate (9 ml.) in ethylene glycol (104ml.) was refluxed for 1 hour with stirring. The mixture was then slowlydistilled until the boiling-point reached 185° and then heated to refluxfor 3 hours. The cooled mixture was treated with water (ca. 300 ml.) andthe product was isolated with ether in the usual manner.Recrystallisation from methanol gave 2-butylfluorene, m.p. 65°-66.5°.

2-Butylfluorene (6.1 g.) was acetylated exactly as described for2-ethylfluorene in the preceding Example 21, using acetic anhydride(3.08 g.) and aluminium chloride (8.66 g.) in dichloroethane. Theproduct was recrystallised from light petroleum to give2-acetyl-7-butylfluorene, m.p. 102° 104.5°. This product (1.98 g.) wasoxidised with sodium hypobromite (from 7.23 g. of bromine and 4.52 g.sodium hydroxide in 160 ml. water) exactly as described for2-acetyl-7-ethylfluorene in the preceding Example. The7-butylfluorenone-2-carboxylic acid thus isolated had m.p. > 300° andwas homogeneous by thin layer chromatography.

EXAMPLE 16 Dipotassium anthraquinone-2,6-dicarboxylate

Anthraquinone-2,6-dicarboxylic acid (1.00g) was dissolved in the minimumquantity of water (20 ml) containing one equivalent of potassiumbicarbonate (0.68g) at the boil. The solution was filtered whilst hotand allowed to crystallise. The product which separated was filteredoff, dried at 100°C, and analysed for the dihydrate. Analysis: RequiredCarbon 47.06, Hydrogen 2.47%; Found Carbon 47.09, Hydrogen 2.48%.

EXAMPLE 17 N,N-Diethylfluorenone-2-carboxamide

A mixture of fluorenone-2-carbonyl chloride (2.4g) and diethylamine(1.5g) in dry benzene (50ml) was heated to reflux for 2 hours. Themixture was allowed to cool and the solid was filtered, washed withbenzene, then with water and dried in vacuo. Recrystallisation fromethanol gave N,N-diethylfluorenone-2-carboxamide, m.p. 90°-92°.

EXAMPLE 18 Dibutyl fluorenone-2,7-dicarboxylate

A suspension of fluorenone-2,7-dicarboxylic acid (6.0g) in dry n-butanol(200ml) with sulphuric acid (2ml) was stirred and heated to reflux.After 4 hours all the solid had dissolved and refluxing was continuedfor another 2 hours and the solution then allowed to cool. Thecrystalline product was removed by filtration, washed with n-butanol,then washed well with water and dried in vacuo to give pure dibutylfluorenone-2,7-dicarboxylate m.p.: 99.5°-100.5°.

EXAMPLE 19 7-Butoxycarbonyl fluorenone-2-carboxylic acid sodium salt

Dibutyl fluorenone-2,7-dicarboxylate (3.8g) was added to a stirredrefluxing solution of sodium hydroxide (400mg.) in dry n-butanol(75ml.). Stirring and refluxing were continued for 10 minutes and themixture was allowed to cool. The crystalline product was filtered,washed with n-butanol and dried in vacuo. The solid was ground withwater (10ml.) and the paste was filtered; this process was repeated andthe solid washed with a little ice-cold water and dried to give pure7-butoxycarbonyl fluorenone-2-carboxylic acid sodium salt monohydrate,m.p. >300°.

EXAMPLE 20 7-Butoxycarbonyl fluorenone-2-carboxylic acid

A portion (1.2g.) of the sodium salt of Example 29 was dissolved in warmwater (40ml.), and the solution was quickly cooled to 20° and treatedwith 2N-hydrochloric acid (2ml.). The precipitated solid was filtered,washed well with water and dried in vacuo to give 7-butoxycarbonylfluorenone-2-carboxylic acid, m.p. 248°-250°.

EXAMPLE 21-23

In the manner described in Examples 18, 19 and 20, were prepared thecorresponding n-propyl esters: Example 21: Dipropylfluorenone-2,7-dicarboxylate, m.p. 146.5°-148°.

Example 22: 7-Propoxycarbonyl fluorenone-2-carboxylic acid sodium saltmonohydrate, m.p. > 300°.

Example 23 7-Propoxycarbonyl fluorenone-2-carboxylic acid, m.p.250°-252°.

EXAMPLE 24 Dihexylfuorenone-2,7-dicarboxylate

A suspension of fluorenone-2,7-dicarboxylic acid (5.0g) in n-hexanol(200 ml.) containing sulphuric acid (2 ml) was heated to reflux for 18hours. The resulting dark solution was washed with water (5 × 75 ml) andthe solid which separated during this washing was filtered, washed witha little n-hexanol and dried in vacuo. This product was dihexylfluorenone-2,7-dicarboxylate, m.p. 89°-90°C; a further quantity wasobtained by evaporating the mother-liquor to low volume under reducedpressure and allowing it to crystallise at 0°C.

EXAMPLE 25 7-Hexyloxyfluorenone-2-carboxylic acid sodium salt

Dihexyl fluorenone-2,7-dicarboxylate (2.18g) was added to a hot solutionof sodium hydroxide (200 mg) in n-hexanol (35 ml) and the mixture wasstirred and refluxed for 5 minutes and then allowed to cool, to 0°C. Theresulting solid was removed by filtration, washed with a littlen-hexanol, dried in vacuo and then ground with water (10ml). Theresulting paste was filtered and the yellow solid was washed with alittle water and dried in vacuo to give7-hexyloxycarbonylfluorenone-2-carboxylic acid sodium salt monohydratem.p. above 300°.

EXAMPLE 26 Fluorenone-2,7-dicarboxylic acid bis-ethanolamine salt

Fluorenone-2,7-dicarboxylic acid (2.68 g.) was suspended in water (10mls) and treated with ethanolamine (1.22 g.). The mixture was warmed andstirred until all the solid had dissolved. The solution was treated withethanol (100 mls), cooled and filtered to remove a small amount ofsolid. The filtrate was evaporated under reduced pressure. The residuewas dissolved in water (2 to 3 mls) and treated with ethanol (100 mls).The solution was cooled to 0°C for 1 hour. The resulting yellowcrystalline solid was filtered, washed with alcohol and dried in vacuoto give Fluorenone-2,7-dicarboxylic acid bis-ethanolamine salt whichdecomposed slowly above 145°C.

EXAMPLE 27 Anthraquinone-2,6-dicarboxylic acid bis-ethanolamine salt

Anthraquinone-2,6-dicarboxylic acid (2.96 g.) was suspended in methanol(50 mls.). Ethanolamine (1.36 g.) was added and the mixture boiled for30 minutes. On cooling the pale yellow solid was filtered off, washedwith methanol, dried at room temperature in vacuo, and analysed for thebis-ethanolamine salt.

Analysis: Required (for C₂₀ H₂₂ N₂ O₈): Carbon 57.41; Hydrogen 5.30; andNitrogen 6.70. Found: Carbon 57.48; Hydrogen 5.33; and Nitrogen 6.70.

EXAMPLE 28 Preparation of 7-Propoxycarbonylfluorenone-2-carboxamide

7-Propoxycarbonylfluorenone-2-carboxylic acid of Example 23 (4 g.) wastreated with thionyl chloride (40 ml.); the mixture was heated underreflux for 2 hours; and the resulting solution was evaporated underreduced pressure to give yellow, crystalline,7-propoxycarbonylfluorenone-2-carbonyl chloride. A portion of this acidchloride (2.1 g.) was stirred at room temperature for 11/2 hours with 2Naqueous ammonia (30 ml.). The resulting solid was filtered, washed withwater, dried and recrystallised from dimethylformamide to give7-propoxycarbonylfluorenone-2-carboxamide, m.pt. 278°-279°C.

EXAMPLE 29 Preparation of 7-carbamoylfluorenone-2-carboxylic acid sodiumsalt

7-Propoxycarbonylfluorenone-2-carboxamide of Example 28 (1.46 g.) wasadded to a solution of sodium hydroxide (190 mg.) in refluxingpropan-1-ol and the mixture heated under reflux, with stirring for 2hours. The mixture was then cooled and the solid filtered, washed with alittle propanol, dried under reduced pressure and then dissolved in warmwater (ca. 20 ml.). The solution was filtered, the filtrate evaporatedunder reduced pressure, and the resulting solid recrystallised fromwater (ca. 5 ml.) to give 7-carbamoylfluorenone-2-carboxylic acid sodiumsalt, m.pt > 300° C.

EXAMPLE 30 Preparation of N,N -Diethyl-7-propoxycarbonylfluorenone-2-carboxamide

7-Propoxycarbonylfluorenone-2-carbonyl chloride [(2.1 g.) prepared as inExample 28] was treated with diethylamine (1 g.) in dry benzene (30 ml.)and the mixture was refluxed for 30 minutes. The resulting solution wascooled, washed twice with water, dried over sodium sulpahte andevaporated to dryness. The crystalline residue, m.pt. 123°-124°C wasrecrystallised from ethanol to give pureN,N-diethyl-7-propoxycarbonylfluorenone-2-carboxamide, m.pt. 124°-125°C.

EXAMPLE 31 Preparation of N,N-Diethyl-7-carbamoylfluorenone-2-carboxylicacid sodium salt

N,N-Diethyl-7-propoxycarbonylfluorenone-2-carboxamide of Example 30 (815mg.) was added to a solution of sodium hydroxide (90 mg.) in refluxingpropan-1-ol (15 ml.). The solid dissolved rapidly and the solution wasallowed to cool over 30 minutes, with stirring. The solid whichseparated on cooling was filtered, washed with a little propanol anddried in vacuo to give N,N-diethyl-7-carbamoylfluorenone-2-carboxylicacid sodium salt m.pt. > 300°C.

EXAMPLE 32 Preparation of N,N-Diethyl-7-carbamoylfluorenone-2-carboxylicacid

N,N-Diethyl-7-carbamoylfluorenone-2-carboxylic acid sodium salt ofExample 31 (190 mg.) was dissolved in water (10 ml.) and the solutionacidified with 2N HC₁ (0.3 ml.) to precipitateN,N-diethyl-7-carbamoylfluorenone-2-carboxylic acid m.p. 247°-248°C.

EXAMPLE 33 Preparation of Fluorenone-2,5-dicarboxylic acid

Acetic anhydride (17.7 g.) was added to a stirred suspension ofaluminium chloride (64 g.) in dichloroethane (100 ml.). The resultingsolution was cooled to 0°C and treated dropwise with stirring, below10°C, with a solution of 4-acetylfluorene (27.86 g.) in dichloroethane(100 ml.). The mixture was stirred at room temperature for 1 hour andthen at 40°C for 3 hours, and finally cooled to 0°C and decomposed with2N hydrochloric acid (200 ml.). The dichloroethane solution wasseparated and the aqueous portion was extracted with chloroform.

The combined organic solution was washed with water and with aqueoussodium bicarbonate, dried over sodium sulphate and evaporated underreduced pressure. The residual solid was twice recrystallised fromethanol to give pure 2,5-diacetylfluorene, m.pt. 128°-129°C. A solutionof sodium hydroxide (27.2 g.) in water (500 ml.) was cooled to 0°C,stirred, and treated dropwise with bromine (14.8 ml.).2,5-Diacetylfluorene (5g.) was added, the temperature was raised to 60°Cover 3 hours and kept at 60°C for 3 hours. The mixture was cooled andfiltered and the filtrate was warmed to 60°C, treated with sodiumacetate (230 g.) and then cooled to 0°C for 1 hour. The resulting yellowprecipitate was dissolved in water (200 ml.) and the solution wasacidified with concentrated hydrochloric acid. After heating on thestream bath for 1 hour the solid was filtered, washed with water anddried in vacuo to give fluorenone-2,5-dicarboxylic acid m.pt. 300°C.

EXAMPLE 34 Preparation of Fluorenone-2,6-dicarboxylic acid

2,6-Diacetylfluorene (m.p. 155°C) was prepared from 3-acetylfluorene andoxidised to fluorenone-2,6-dicarboxylic acid (m.p.>300° C) in the mannerdescribed in Example 33.

EXAMPLE 35 N,N-dibutyl-7-carbamoylfluorenone-2-carboxylic acid sodiumsalt

7-Propoxycarbonylfluorenone-2-carbonyl chloride (2.1g.) and dibutylamine(1.73g.) were refluxed in dry benzene (25 ml); the solid dissolvedwithin 4 minutes and refluxing was continued for a total of 30 minutes.The solution was cooled, washed twice with water, dried over sodiumsulphate and evaporated under reduced pressure. The resulting yellow gumwas dissolved in propan-1-ol (15 ml) and the solution was added to a hotsolution of sodium hydroxide (256 mg) in hot propan-1-ol (25 ml). Themixture was kept at 80°C. for 5 minutes and then evaporated to halfvolume and allowed to cool. The resulting yellow crystalline solid wasfiltered, washed with propanol, and dried to give pureN,N-dibutyl-7-carbamoylfluorenone-2-carboxylic acid sodium salt, m.p. >300°C.

EXAMPLE 36 7-Propoxycarbonylfluorenone-2-carbonitrile

7-Propoxycarbonylfluorenone-2-carboxamide (318g.) was dissolved in warmdimethylformamide (50 ml.) and the solution was stirred and cooled to-25°C. Thionyl chloride (7.55 ml.) was added dropwise over 10 minutes tothe stirred mixture which was then stirred at 0°C. for 3 hours and leftto stand at 0°C. for 48 hours. The mixture was treated with ice waterand the resulting yellow precipitate was filtered, washed with water anddried in vacuo to give pure 7-propoxycarbonylfluorenone-2-carbonitrilem.p. 198°-199°C.

EXAMPLE 37 7-(2-Butoxycarbonyl)fluorenone-2-carboxylic acid

A suspension of fluorenone-2,7-dicarboxylic acid (10g.) in butan-2-ol(300 ml.) containing sulphuric acid (3 ml.) was heated to reflux for 4days. The yellow solution was cooled and the resulting yellow solid wasfiltered, washed well with butan-2-ol and dried to give pure di-2-butylfluorenone-2-carboxylate m.p. 118°-119°C. This diester (3.04g.) wasadded in one portion to a hot solution of sodium hydroxide (320 mg.) inbutan-2-ol (50 ml.) containing 1 drop of water. The mixture was stirredat reflux temperature for 10 minutes and then allowed to cool to roomtemperature. The resulting yellow solid was filtered, washed withbutan-2-ol and then dissolved in water (15 ml.). The aquous solution waskept at 4°C. overnight, filtered to remove a small amount of solid, andcarefully acidified with 2N hydrochloric acid. The yellow precipitatewas filtered, washed with water and dried to give pure7-(2-butoxycarbonyl)fluorenone-2-carboxylic acid m.p. 266°-267°C.

EXAMPLE 38 Dimethyl anthraquinone-2,6-dicarboxylate

Anthraquinone-2,6-dicarboxylic acid (1.0g.) was boiled under reflux withthionyl chloride (10 ml.) and dimethylformamide (0.1 ml.) for 45minutes. The resulting clear solution was evaporated to dryness andmethanol (20 ml.) was added. The suspension was boiled for 1 hour,cooled, and the yellow product filtered off and recrystallised fromdimethylformamide, to give, after drying at 80°C. in vacuo, the diester,m.p. 260°C.

EXAMPLE 39 Anthraquinone-2,6-dicarboxamide

Anthraquinone-2,6-dicarboxylic acid (5.0 g.) was boiled with thionylchloride (50 ml.) and dimethylformamide (0.25 ml.) for 45 min. Theresulting clear solution was evaporated to dryness and the residual acidchloride treated with 0.880 ammonia. After standing for 30 minutes, thecrude amide was filtered off, washed with water and dried, m.p. 420°(decomp.).

    Example A - Aerosol Powder                                                    ______________________________________                                        Disodium fluorenone-2,7-dicarboxylate                                                                     2.0 g                                             (Micronised)                                                                  Span 85 (Trade Name for Sorbitan Trioleate)                                                               40.0 mg                                           Saccharin Sodium (micronised)                                                                             20.0 mg                                           Menthol                     20.0 mg                                           Arcton 11 (Trade Name)      45.0 g                                            Arcton 12 (Trade Name)    to                                                                              100.0 ml                                          ______________________________________                                    

The Disodium Carboxylate salt was micronised in a 3 inch Cox FluidEnergy Mill using an air pressure of about 7.10⁵ Newton/meter² at a feedrate of about 60 g of the salt per hour. In the resulting micronisedpowder, 93% by weight of the particles had a diameter not less than 2μand 98% by number of the particles had a diameter of not more than 7μ.

The Span 85 and Menthol were dissolved in Arcton 11 (Trade Name) andcooled to approximately 10°C. The micronised Disodium carboxylate saltand micronised Sodium saccharin were dispersed in the cooled solutionand the resulting suspension was cooled to approximately -40°C. TheArcton 12, cooled to -40°C, was then added and the resulting suspensionstirred with cooling.

The suspension was filled into suitable 10 ml aluminium containers eachof which was closed with a 100μ1 metered dose valve.

The composition provides 2 μg of the Disodium carboxylate salt in each100μ1 dose.

    ______________________________________                                        Example B - Nasal Drops.                                                      ______________________________________                                        Disodium fluorenone-2,7-dicarboxylate                                                                     0.5 g                                             Chlorbutol                  0.5 g                                             Sodium Chloride             0.5 g                                             Distilled Water        to   100.0 ml                                          ______________________________________                                    

The ingredients were dissolved together in Distilled Water (95 ml) atroom temperature. The solution was made up to volume with the balance ofthe Distilled Water and clarified by passage through a filter ofsintered glass, porosity No. 4.

    ______________________________________                                        Example C - Nasal Drops.                                                      ______________________________________                                        Fluorenone-2,7-dicarboxylic acid                                                                          0.5 g                                              (micronised powder)                                                          Hypromellose 50             0.6 g                                             Chlorbutol                  0.5 g                                             Sodium Chloride             0.5 g                                             Distilled Water       to    100.0 ml                                          ______________________________________                                    

Chlorbutol was dissolved in Distilled Water (30 ml) at 75°C.Hypromellose was added and dispersed. An ice-cold solution of sodiumchloride in distilled Water (60 ml) was added, and the mixture stirreduntil Hypromellose dissolved completely. The fluorenone acid was addedand thoroughly dispersed, and the mixture diluted to volume.

    ______________________________________                                        Example D - Eye Drops.                                                        ______________________________________                                        Disodium fluorenone-2,7-dicarboxylate                                                                     0.20 g                                            Sodium Chloride             0.83 g                                            Methyl Hydroxybenzoate      0.06 g                                            Propyl Hydroxybenzoate      0.04 g                                            Distilled Water       to    100.00 ml                                         ______________________________________                                    

Methyl and Propyl Hydroxybenzoate were dissolved in Distilled Water (70ml) at 75°C. Sodium Chloride was added and dissolved and the solutionallowed to cool. Disodium salt was added and dissolved, and the finalsolution made up to volume and sterilised by filtration.

    ______________________________________                                        Example E - Capsules of Powder                                                ______________________________________                                        Disodium fluorenone-2,7-dicarboxylate                                                                      4.0 mg                                            (0.5 to 7.0μ powder)                                                      Lactose (30-90μ powder)   46.0 mg                                          ______________________________________                                    

The powders were mixed until homogenous and filled in suitable size hardgelatin capsules, 50 mg per capsule, for use in a powder inhalationdevice, such as the type described in U.K. Pat. No. 1,182,779.

    ______________________________________                                        Example F - Lotion for Topical Use.                                           ______________________________________                                        Disodium fluorenone-2,7-dicarboxylate                                                                       1.5 g                                           Sorbitan Monolaurate          0.6 g                                           Polysorbate 20                0.6 g                                           Cetostearyl Alcohol           1.2 g                                           Glycerin                      6.0 g                                           Methyl Hydroxybenzoate     to 0.2 g                                           ______________________________________                                    

To a solution of Methyl Hydroxybenzoate and Glycerin in Distilled Water(70 ml) at 75°C was added a mixture of Sorbitan Monolaurate, Polysorbate20 and Cetostearyl Alcohol at the same temperature. The resultingemulsion was homogenised using high speed stirring and allowed to cool.A solution of the Disodium salt in the remaining Distilled Water wasadded and the whole stirred.

    ______________________________________                                        Example G - Injection Solution                                                ______________________________________                                        Disodium fluorenone-2,7-dicarboxylate                                                                      10.0 mg                                          Water for Injection     to   1.0 ml                                           ______________________________________                                    

The Disodium Salt was dissolved in half the Water for Injection. Theremaining Distilled Water was added and the solution sterilised byfiltration. The sterile solution was filled into an ampoule underaseptic conditions.

    ______________________________________                                        Example H - Aerosol Powder                                                    ______________________________________                                        Disodium fluorenone-2,7-dicarboxylate                                                                     400 mg                                            Sorbitan Trioleate          200 mg                                            Trichlorofluoromethane      4.5 g                                             Dichlorodifluoromethane   to                                                                              10.0 ml                                           ______________________________________                                    

Sorbitan Trioleate was dissolved in Trichlorofluoromethane. Disodiumsalt was added and thoroughly dispersed. The mixture was transferred toa suitable aerosol canister and Dichlorodifluoromethane injected throughthe valve system. The composition provides 4 mg of Disodium salt in each100μ1 dose.

    ______________________________________                                        Example I - Aerosol Powder                                                    ______________________________________                                        Fluorenone-2,7-dicarboxylic acid (0.5-7μ powder)                                                       500 mg                                            Sorbitan Trioleate          100 mg                                            Saccharin (6-10μ powder) 5 mg                                              Methanol                    2 mg                                              Sodium Sulphate (2-6μ powder)                                                                          50 mg                                             Trichlorofluoromethane      4.5 g                                             Dichlorodifluoromethane   to                                                                              10.0 ml                                           ______________________________________                                    

Sorbitan Trioleate and Methanol was dissolved in Trichlorofluoromethane.Acid, Saccharin and Sodium Sulphate were added and dispersed. Thesuspension was transferred to a suitable aerosol canister.Dichlorodifluoromethane was injected through the valve system. Thecomposition provides 5 mg of Acid in each 100μ1 dose.

    ______________________________________                                        Example J - Lozenge                                                           ______________________________________                                        Disodium fluorenone-2,7-dicarboxylic acid                                                                  50 mg                                            Mannitol                     400 mg                                           Dextrose Monohydrate         400 mg                                           Magnesium Stearate           20 mg                                            Granulated with a solution of Polyvinyl-                                       pyrrolidone;                                                                 5% in 25% Alcohol.                                                            ______________________________________                                    

A mixture of Disodium Salt, Mannitol and Dextrose Monohydrate wasgranulated with Polyvinylpyrrolidone in Alcohol, and the granule dried.Magnesium Stearate was sifted on and the mixture compressed to producelozenges of the desired shape.

EXAMPLE K Pharmaceutical Compositions

Pharmaceutical compositions of dimethylfluorenone-2,7-dicarboxylate wereprepared from the same carrier ingredients and in similar manner tothose described in Examples C and I.

EXAMPLE L Pharmaceutical Compositions

Pharmaceutical compositions of anthraquinone-2,6-dicarboxylic acid wereprepared from the same carrier ingredients and in similar manner tothose described in Examples C and I.

What we claim is:
 1. A method of preventing the symptoms of asthma orallergic rhinitis in a mammal having asthma or allergic rhinitis whichcomprises administering to said mammal a prophylactically effectiveamount of a compound of formula ##SPC14##where Z¹ is selected from thegroup consisting of carboxyl, a pharmaceutically acceptable carboxylatesalt and alkyl carboxylate wherein the alkyl moiety has 1 to 6 carbonatoms; and Z² is selected from the group consisting of hydrogen and asubstituent Z¹ as defined herein.
 2. A method of preventing the symptomsof asthma or allergic rhinitis in a mammal having asthma or allergicrhinitis which comprises administering to said mammal a prophylacticallyeffective amount of a compound of the formula ##SPC15##wherein Z¹ and Z²are the same or different and each is selected from the group consistingof carboxyl, pharmaceutically acceptable carboxylate salt, and alkylcarboxylate having 1 to 6 carbon atoms in the `alkyl` moiety.
 3. Themethod as claimed in claim 2 wherein Z¹ is selected from the groupconsisting of carboxyl and pharmaceutically acceptable carboxylate salt,and Z² is selected from Z¹ as defined herein.
 4. The method as claimedin claim 3 wherein the carboxylate salt is selected from the groupconsisting of potassium, sodium, calcium, magnesium, ammonium andorganic base salts selected from the group consisting oftriethanolamine, diethylaminoethylamine, piperazine and morpholine. 5.The method according to claim 1 wherein the compound is administered byinhalation.
 6. The method according to claim 5 wherein the compound isadministered in the form of a powder having a particle size in the rangefrom 0.5 to 7μ.
 7. The method according to claim 1 wherein the amount ofthe compound is from 2 μg. to 100 mg. per Kg. bodyweight of said mammal.8. The method according to claim 1 wherein the amount of the compound isfrom 20 μg to 0.2 mg. per kg. bodyweight of said mammal.
 9. The methodaccording to claim 1 wherein the asthma condition is extrinsic asthma.10. The method according to claim 1 wherein the condition is allergicrhinitis.
 11. The method of claim 1 wherein said compound is disodiumanthraquinone-2,6-dicarboxylate.